JPWO2016088863A1 - Crystals of diazabicyclooctane derivatives and methods for producing stable lyophilized formulations - Google Patents

Abstract

An object of the present invention is to provide a method capable of easily producing crystals of compound (I) on an industrial scale, and a stable lyophilized composition of compound (I). By freeze-drying an aqueous solution containing Compound (I) and an inorganic salt such as sodium chloride, a freeze-dried composition having excellent storage stability in which Compound (I) is a crystal can be obtained. Even without this, it was found that crystals of compound (I) can be obtained from the aqueous solution.

Description

  The present invention relates to a method for producing a crystal of a diazabicyclooctane derivative represented by the formula (I), a composition of the derivative, a lyophilized preparation, and a method for producing the same.

  Novel diazabicyclooctane derivatives represented by the following formula (I): (2S, 5R) -N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2 .1] Octane-2-carboxamide (hereinafter also referred to as “compound (I)”) is a β-lactamase inhibitor, and is disclosed in WO2013 / 180197 (Patent Document 1).

As a method for obtaining a crystalline lyophilized composition, a method in which an aqueous drug solution is frozen at a predetermined temperature and then heated to a predetermined temperature and held at a constant temperature (hereinafter referred to as a heat treatment step) is disclosed. (Patent Document 2).
Patent Document 3 and Patent Document 4 describe that an inorganic salt can be added to a chemical solution in a freeze-drying method including a heat treatment step.
Patent Document 5 discloses a method for obtaining an aqueous drug solution containing 2 to 10% (V / V) alcohol having 1 to 3 carbon atoms or acetone as a crystalline lyophilized composition by a lyophilization method including a heat treatment step. ing.
Patent Document 6 discloses a crystal of compound (I) and a production method thereof.

WO2013 / 180197 Japanese Patent Publication No. 03-74643 Japanese Patent No. 2844344 Japanese Patent No. 2767171 Japanese Patent Publication No. 60-19759 WO2015 / 053297

When compound (I) is lyophilized under general conditions that undergo a freezing step followed by a vacuum drying step, compound (I) becomes amorphous and its chemical stability is significantly lower than its crystalline state, Our study confirmed that it was difficult to obtain a freeze-dried composition with excellent storage stability. Considering production and distribution, a stable lyophilized composition of Compound (I) has been strongly demanded.
However, even when the aqueous solution of Compound (I) was lyophilized by the method of Patent Document 2, a crystalline lyophilized composition could not be obtained. In the example of Patent Document 3, it is shown that a crystalline lyophilized composition can be obtained regardless of whether or not an inorganic salt is added, and the addition of an inorganic salt in crystallization is not essential. Furthermore, it is disclosed that in the case of normal lyophilization conditions that do not include a heat treatment step, the addition of an inorganic salt leads to an increase in the amorphous portion and adversely affects crystallization. In Patent Document 4, a heat treatment process is always incorporated, and there is no example in which an inorganic salt is added. The method of Patent Document 5 is not desirable as an industrial production method because of concern about residual solvent.
Thus, no method has yet been found for obtaining a crystalline lyophilized composition under lyophilization conditions that do not involve a heat treatment step or addition of an organic solvent.
On the other hand, in the method of Patent Document 6, sufficient crystals cannot be obtained unless the aqueous solution containing the compound (I) is once purified by a column or the like.
It was also an issue to obtain a single crystal form, particularly a stable form I, by controlling the crystal polymorph.
For this reason, there has been a strong demand for a method capable of easily producing a crystal of compound (I) on an industrial scale, and further a method capable of producing a single crystal form of compound (I), particularly an I-type crystal.

  The present invention relates to a method capable of producing crystals of compound (I), particularly a single crystal form, in particular, stable form I crystals, on an industrial scale, and a stable lyophilized composition of compound (I). The purpose is to provide goods.

  In view of this, the inventors have intensively studied to develop a freeze-dried composition of Compound (I) having excellent storage stability, and as a result, freeze-drying an aqueous solution containing Compound (I) and an inorganic salt such as sodium chloride. Compound (I) is crystallized, and as a result, a freeze-dried composition having excellent storage stability in which Compound (I) is a crystal, particularly a single crystal form, particularly a stable Form I crystal, is obtained. Further, it was found that crystals of compound (I), particularly a single crystal form, particularly a stable form I crystal, can be obtained from the aqueous solution without lyophilization, and the present invention has been completed. It was.

That is, the present invention relates to a method for producing a crystal of compound (I), which comprises crystallizing compound (I) from an aqueous solution containing compound (I) and an inorganic salt such as sodium chloride. .
The present invention also provides a method for producing a lyophilized composition containing compound (I), which comprises crystallizing compound (I) by the method for producing a crystal of compound (I); A method for producing a lyophilized composition comprising (I), comprising crystallization of compound (I) by lyophilizing an aqueous solution comprising compound (I) and an inorganic salt such as sodium chloride. And a freeze-dried composition characterized in that it comprises crystals of compound (I) and an inorganic salt such as sodium chloride. The lyophilized composition of the present invention can be produced by the method for producing the lyophilized composition of the present invention.

  In the present invention, for example, compound (I) is prepared by a general method such as adding a seed crystal to an aqueous solution containing compound (I) and an inorganic salt such as sodium chloride and then adding a poor solvent as necessary. Is crystallized. Alternatively, the compound (I) is crystallized by freeze-drying an aqueous solution containing the compound (I) and an inorganic salt such as sodium chloride. By including an inorganic salt such as sodium chloride, a crystal of compound (I), particularly the same type I crystal as in Patent Document 6, can be obtained, and the storage stability can be dramatically improved as compared with the amorphous state. it can.

  The form I crystal of the present invention is the same as the form I crystal of Patent Document 6, and has a characteristic powder X-ray diffraction peak pattern as shown in Table 1 or FIG. In the present invention, powder X-ray diffraction is measured by the method described in Test Example 1.

  In the present invention, an aqueous solution containing compound (I) and an inorganic salt such as sodium chloride is freeze-dried, for example, freeze-dried under general conditions that undergo a freezing step followed by a reduced-pressure drying step. That is, the present invention includes subjecting an aqueous solution containing compound (I) and an inorganic salt such as sodium chloride to a freezing step, and subjecting the frozen product obtained in the freezing step to a vacuum drying step. The present invention also relates to a method for producing a lyophilized composition containing compound (I). By including an inorganic salt such as sodium chloride, a freeze-dried composition in which compound (I) is crystallized, in particular, crystallized into I-type crystal, is obtained, and the storage stability is drastically compared with the amorphous state. Can be improved.

  In the present invention, a freeze-dried composition in which compound (I) is crystallized can be obtained without including a heat treatment step and a refreezing step between the freezing step and the reduced-pressure drying step. That is, in the method for producing a lyophilized composition of the present invention, the heat treatment and refreezing operation of the frozen product obtained in the freezing step may not be performed. In general, lyophilization is a production method that requires a long time for production. A method for obtaining a crystalline lyophilized composition by including a heat treatment step and a refreezing step between the freezing step and the reduced-pressure drying step is known, but the problem is that the production time is further increased and the productivity is low. It is. In the present invention, a freeze-dried composition in which compound (I) is crystallized can be obtained without including a heat treatment step and a re-freezing step between the freezing step and the reduced-pressure drying step. Can be increased.

  In the present invention, a heat treatment step and a refreezing step can be incorporated between the freezing step and the vacuum drying step. That is, the present invention is obtained by subjecting the frozen material obtained in the freezing step to a heat treatment step, subjecting the heat treated material obtained in the heat treatment step to a refreezing step, and the refreezing step. The present invention also relates to the above-mentioned method for producing a lyophilized composition containing compound (I), which further comprises subjecting a frozen product to the vacuum drying step. By incorporating a heat treatment step, the crystallization efficiency of compound (I) can be further improved.

  In the present invention, by crystallizing from an aqueous solution containing compound (I) and an inorganic salt, crystals of compound (I) can be obtained without purifying compound (I) in advance using a column or the like. On the industrial scale, it is possible to easily produce crystals of compound (I), in particular, a single crystal form, in particular a stable form I crystal. Further, the present invention provides a freezing characterized in that the compound (I) is a crystal, particularly a single crystal form, particularly a form I crystal, by lyophilization from an aqueous solution containing the compound (I) and an inorganic salt. A dry composition is obtained, and a lyophilized preparation of compound (I) having excellent storage stability can be provided.

The powder X-ray diffraction chart of the lyophilized composition obtained in Example 1a is shown. The powder X-ray-diffraction chart of the lyophilized composition obtained in Example 1b is shown. The powder X-ray-diffraction chart of the crystal | crystallization obtained in Example 2b is shown. The powder X-ray diffraction chart of the freeze-dried composition obtained in Comparative Example 1 is shown. The powder X-ray-diffraction chart of sodium chloride is shown.

The inorganic salt used in the present invention is not particularly limited as long as it can be added to an injection. Sodium chloride, magnesium chloride, calcium chloride, potassium chloride, ammonium chloride, sodium bromide, calcium bromide, bromide Examples include potassium, tetrabutylammonium bromide, magnesium sulfate, sodium iodide, potassium iodide, sodium hydrogen phosphate, sodium acetate, sodium citrate, sodium tartrate, sodium glutamate, and Rochelle salt (sodium potassium tartrate). In view of crystallization efficiency, sodium chloride, magnesium chloride, magnesium sulfate, sodium citrate, sodium glutamate, and Rochelle salt (potassium sodium tartrate) are preferable. It has been confirmed that any of these inorganic salts can be used to obtain Form I crystals of Compound (I). Particularly preferred is sodium chloride. Although there is no restriction | limiting in particular in the compounding quantity to the freeze-dried composition and pharmaceutical formulation of the inorganic salt of this invention, Preferably it is 0.1-10 molar equivalent with respect to compound (I), More preferably, it is 1-2 mol Is equivalent. This is because the crystallization efficiency is lowered in both cases where the blending amount is small and large, which affects the stability of the preparation.
In addition, when crystallization is performed from an aqueous solution containing the compound (I) and an inorganic salt, the amount of the inorganic salt added to the aqueous solution is not particularly limited, but preferably 0.1 to 0.1% of the compound (I). 10 molar equivalents, more preferably 0.5 to 1.5 molar equivalents.

  In the present invention, the concentration of the compound (I) in the aqueous solution before crystallization or before lyophilization is usually 1% (W / W) to 40% (W / W), preferably 2.5% (W / W W) to 20% (W / W), more preferably 7.5% (W / W) to 10% (W / W). This is because when the concentration is low, the crystallization efficiency is lowered, affecting the stability of the preparation, and when the concentration is high, precipitation from the supersaturated solution is likely to occur.

  The aqueous solution containing the compound (I) of the present invention and the inorganic salt may be prepared by dissolving the compound (I) and the inorganic salt together in water, or one of them may be dissolved in water first. It is also possible to obtain an aqueous solution and dissolve the remaining one therein to prepare.

In the present invention, for example, the compound (I) is crystallized by adding a seed crystal to an aqueous solution containing the compound (I) and an inorganic salt, if necessary, and then adding a poor solvent.
Here, as the seed crystal, the seed crystal of compound (I) can be used. For example, the I-type crystal of Patent Document 6 can be used. Alternatively, a freeze-dried product obtained by freeze-drying an aqueous solution containing compound (I) and an inorganic salt may be used as a seed crystal. The amount of the seed crystal is 0 to 20 wt%, preferably 0.01 to 2 wt%.

  Examples of the poor solvent include alcohols such as methanol, ethanol, 1-propanol, and isopropanol, acetone, acetonitrile, and tetrahydrofuran, and alcohols such as methanol, ethanol, 1-propanol, and isopropanol are preferable. The amount of the poor solvent is adjusted from the solubility so that the isolation loss is 1% or less, for example, 1 to 10 times the amount of the initial solution of the aqueous solution containing the compound (I) and the inorganic salt, preferably Is used in an amount of 3 to 7.5 times, more preferably 5 to 7.5 times. The timing of adding the poor solvent is not particularly limited. For example, in the case of I-type crystals, the mixture is added dropwise after the mixture after inoculation becomes a slurry. The time required for the addition of the poor solvent is not particularly limited, but is, for example, 30 minutes or longer, preferably 1 hour or longer.

In the present invention, the compound (I) may be crystallized after adjusting the temperature of the aqueous solution containing the compound (I) and the inorganic salt.
The stirring time depends on the deposition rate, but is stirred for 1 to 24 hours, preferably 1 to 15 hours.
Crystals of compound (I) can be obtained by subjecting the precipitated crystals to normal filtration, washing, air drying, or vacuum drying. In the case of solvated crystals, overdrying is avoided by management means such as product temperature, loss on drying, humidified vacuum drying, humidified air drying.

  In the present invention, compound (I) may be crystallized by lyophilizing an aqueous solution containing compound (I) and an inorganic salt. The present invention also relates to a method for producing a freeze-dried composition containing compound (I), wherein the compound (I) is crystallized by freeze-drying an aqueous solution containing compound (I) and an inorganic salt. It also relates to the manufacturing method including.

  In the present invention, for example, an aqueous solution containing compound (I) and an inorganic salt is subjected to ordinary freeze-drying including a freezing step and a reduced-pressure drying step. The cooling temperature for freezing the aqueous solution is affected by the concentration of compound (I) or the concentration of the inorganic salt, but is usually −60 ° C. to −10 ° C., preferably −50 ° C. to −10 ° C., more preferably It is −50 ° C. to −15 ° C. Although there is no restriction | limiting in particular in the speed | rate at the time of carrying out cooling freezing, Usually, it carries out over 0.25 hours-5 hours. Note that the frozen material obtained in the freezing step can be held for a certain period of time at the freezing temperature until the next reduced-pressure drying step after freezing.

  The vacuum drying step to which the frozen product obtained in the freezing step is attached may be divided into a primary drying (sublimation) step and a secondary drying (dehumidification) step. The primary drying step is carried out under normal reduced pressure, and the temperature is affected by the concentration of compound (I) and the concentration of inorganic salt, but cannot be specified, but the product temperature may be set to a condition that does not exceed the collapse temperature of the frozen material. desirable. Although the time varies depending on the temperature setting and production scale, it cannot be specified, but it can be usually performed for 2 hours to 7 days, preferably 5 hours to 72 hours while confirming the transition of the product temperature and the degree of vacuum. The secondary drying step is performed under a normal reduced pressure, and the temperature can be, for example, 10 ° C to 60 ° C, preferably 25 ° C to 60 ° C. Although the time varies depending on the temperature setting and production scale, it cannot be specified, but it can usually be performed for 2 hours to 72 hours, preferably 5 hours to 20 hours while confirming the transition of the product temperature and the degree of vacuum.

  In the present invention, in order to increase the crystallization efficiency, a heat treatment step and a refreezing step can be incorporated between the freezing step and the vacuum drying step. Although the temperature at the time of heat treatment of the frozen material obtained in the freezing step is affected by the concentration of compound (I) and the concentration of inorganic salt, it is carried out at a temperature at which the frozen state can be maintained, preferably -40 to 0 ° C, More preferably, it is -20--4 degreeC. Although the heat treatment time varies depending on the set temperature and the production scale, it cannot be specified, but it can usually be carried out for 0.5 hour to 72 hours, preferably 1 hour to 24 hours. The cooling temperature in the refreezing step to which the heat-treated product obtained in the heat treatment step is attached is usually -60 ° C to -10 ° C, preferably -50 ° C to -10 ° C, more preferably -50 ° C to -15 ° C. It is. Although there is no restriction | limiting in particular in the speed | rate at the time of carrying out cooling freezing, Usually, it carries out over 0.25 hours-5 hours. The frozen product obtained in the refreezing step is subjected to the reduced-pressure drying step.

  When used as a medicament, the crystal and lyophilized composition of the present invention may be administered per se (as is), or may be administered as a conventional pharmaceutical preparation. The pharmaceutical preparation contains pharmaceutically acceptable additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, and diluents as long as the effects of the present invention are not impaired. May be included. Such pharmaceutical preparations include tablets, capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions, transdermal absorption agents, suppositories, ointments, lotions, inhalants, injections, etc. Is exemplified. The crystal and lyophilized composition of the present invention and the pharmaceutical preparation are orally or parenterally (intravenous administration, intramuscular administration, intraperitoneal administration, transdermal administration, airway administration, intradermal administration, subcutaneous administration, etc.) Can be administered.

  In addition to compound (I) which is a β-lactamase inhibitor, β-lactam antibiotics can be added to the pharmaceutical preparation of the present invention. For example, piperacillin, ampicillin, benzylpenicillin, cefoperazone, cefazolin, cephalotin, cefotiam, cefminox, cefmethazole, fromoxef, cefodizime, cefotaxime, ceftriaxone, cefmenoxime, ratamoxef, ceftazimepefemepenecemepefem Biapenem, meropenem, and pharmacologically acceptable salts and solvates thereof can be blended.

  In the injection of the present invention, additives that can be added to normal injections can be appropriately blended. For example, for pH adjustment purposes, inorganic acids such as hydrochloric acid and phosphoric acid or salts thereof, citric acid, malic acid, tartaric acid, organic acids such as succinic acid or salts thereof, arginine, alanine, aspartic acid, histidine, glycine Etc., alkaline substances such as sodium hydroxide and sodium hydrogen carbonate can be blended. For the purpose of adjusting the osmotic pressure, glucose, mannitol, xylitol, sorbitol, sucrose, lactose, maltose, trehalose, dextran and the like can be blended. For the purpose of improving solubility, in addition to polyols such as polyethylene glycol and glycerin, surfactants such as polysorbate, sorbitan sesquioleate, polyoxyethylene polyoxypropylene glycol, and polyoxyethylene hydrogenated castor oil are added. It is also possible to do.

  EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples.

Example 1 Lyophilized Composition of Compound (I) Example 1a
700 mg of compound (I) and 126.1 mg of sodium chloride were dissolved in distilled water to make a total amount of 7 g. The drug solution was filtered through a membrane filter (MILLEX (registered trademark) LG SLLGH13NH: Merck Millipore) having a pore size of 0.20 μm, filled in 1 g in a 5 mL glass vial, and then half-plugged with a rubber stopper. The vial filled with the drug solution was placed in a freeze dryer (DFM-05B-S: ULVAC), the shelf temperature of the freeze dryer was set to 5 ° C., and the vial was cooled under normal pressure for 1 hour. Thereafter, the shelf temperature of the freeze dryer was cooled to −40 ° C. over 1 hour to freeze the drug solution, and this temperature was maintained for 3 hours. Subsequently, the pressure in the freeze dryer was about 10 Pa, the shelf temperature of the freeze dryer was raised to −10 ° C. over 6 hours, and this state was maintained for 30 hours. Thereafter, the pressure in the freeze dryer was 10 Pa or less, the shelf temperature of the freeze dryer was raised to 25 ° C. over 7 hours, and this state was maintained for 15 hours. After the drying, the inside of the freeze dryer was returned to normal pressure using nitrogen gas and plugged with a rubber stopper. The vial was taken out from the lyophilizer and the aluminum cap was tightened to obtain a lyophilized composition in which Compound (I) was Form I crystals. As sodium chloride, reagent-grade sodium chloride manufactured by Nacalai Tesque was used.

Example 1b
600 mg of compound (I) and 129.7 mg of sodium chloride were dissolved in distilled water to make a total amount of 6 g. The drug solution was filtered through a membrane filter (MILLEX (registered trademark) LG SLLGH13NH: Merck Millipore) having a pore size of 0.20 μm, filled in 1 g in a 5 mL glass vial, and then half-plugged with a rubber stopper. The vial filled with the chemical solution was put into a freeze dryer (console 12-3-ST-CR: Vertis), the shelf temperature of the freeze dryer was set to 5 ° C., and cooled under normal pressure for 1 hour. Thereafter, the shelf temperature of the freeze dryer was cooled to −40 ° C. over 2.5 hours to freeze the chemical solution, and this temperature was maintained for 1 hour. Subsequently, the shelf temperature of the freeze dryer was raised to −4 ° C. over 0.5 hours, and this temperature was maintained for 15 hours. Thereafter, the shelf temperature of the freeze dryer was cooled to −40 ° C. over 2 hours to refreeze the chemical solution, and this temperature was maintained for 0.5 hour. Subsequently, the pressure in the freeze dryer was set to 10 Pa or less, the shelf temperature of the freeze dryer was raised to −10 ° C. over 0.5 hours, and this state was maintained for 20 hours. Thereafter, the shelf temperature of the freeze dryer was raised to 25 ° C. over 0.5 hours, and this state was maintained for 3 hours. After completion of drying, the inside of the freeze dryer was returned to normal pressure and plugged with a rubber stopper. The vial was taken out from the freeze dryer and the aluminum cap was tightened to obtain a freeze-dried composition in which Compound (I) was Form I crystals.

Example 2 Form I crystal of compound (I) Example 2a
1.0 g of compound (I) Form III crystals was dissolved in 10 mL of deionized water. To the obtained solution, 0.18 g of sodium chloride was added and dissolved at room temperature. The solution was cooled to 0 ° C. and then microfiltered. After 45 mL of cooled isopropanol was added dropwise over 1 hour, the mixture was stirred overnight. The resulting crystals were separated and dried under reduced pressure at room temperature for 0.5 hours to obtain 0.82 g of compound (I) crystals (yield 82.0%, Form I crystals).

Example 2b
After 1.71 g of sodium chloride was dissolved in 100 mL of deionized water, 10 g of compound (I) was added and dissolved at room temperature. The solution was cooled to 0 to 5 ° C. and subjected to microfiltration, and then 50 mg (0.5 wt%) of Form I crystals of compound (I) obtained in Example 2a were added, and the mixture was heated at 0 to 5 ° C. for 1 hour. Stir. 500 mL of cooled isopropanol was added dropwise over 1 hour or more and stirred overnight, and then the crystals were separated. The obtained crystals were dried under reduced pressure at room temperature for 0.5 hours to obtain 9.53 g of compound (I) crystals (yield 94.8%, Form I crystals).

Comparative Example 1 Lyophilized composition of Compound (I) The same procedure as in Example 1 was performed, except that sodium chloride was not blended. That is, 700 mg of compound (I) was dissolved in distilled water to make the total amount 7 g. The drug solution was filtered through a membrane filter (MILLEX (registered trademark) LG SLLGH13NH: Merck Millipore) having a pore size of 0.20 μm, filled in 1 g in a 5 mL glass vial, and then half-plugged with a rubber stopper. The vial filled with the drug solution was placed in a freeze dryer (DFM-05B-S: ULVAC), the shelf temperature of the freeze dryer was set to 5 ° C., and the vial was cooled under normal pressure for 1 hour. Thereafter, the shelf temperature of the freeze dryer was cooled to −40 ° C. over 1 hour to freeze the drug solution, and this temperature was maintained for 3 hours. Subsequently, the pressure in the freeze dryer was about 10 Pa, the shelf temperature of the freeze dryer was raised to −10 ° C. over 6 hours, and this state was maintained for 30 hours. Thereafter, the pressure in the freeze dryer was set to 10 Pa or less, the shelf temperature of the freeze dryer was raised to 25 ° C. over 7 hours, and this state was maintained for 15 hours. After the drying, the inside of the freeze dryer was returned to normal pressure using nitrogen gas and plugged with a rubber stopper. The vial was taken out from the lyophilizer and the aluminum cap was tightened to obtain a lyophilized composition in which Compound (I) was amorphous.

Comparative Example 2 Form I Crystal of Compound (I) (Production Method Using Octadecyl Silica Gel or Resin Column Purification)
Comparative Example 2a
0.5M acetic acid buffer (pH 5.5, 35 mL) is ice-cooled, compound (I) (36 g) and a cooled 5M aqueous sodium hydroxide solution are added alternately to adjust the pH to 5.5, and an octadecyl silica gel column. Chromatography (3.6 L) was eluted with water. The active fractions were collected and concentrated under reduced pressure at a water bath temperature of 35 ° C., and the precipitated crystals were vacuum-dried overnight. After pulverizing 2.10 g of the obtained crystals, isopropanol / water (19/1, 13 mL) was added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. The suspension was filtered, washed with cold isopropanol / water (19/1, 80 mL), and the crystals obtained were dried by vacuum pumping to obtain 1.68 g of Form I crystals of Compound (I) ( Yield 80%). DSC endothermic peak 111 ° C. Solubility in 60% aqueous isopropanol; 0.44% (10 ° C), 0.48% (20 ° C).

Comparative Example 2b
Compound (I) (net 4.253 g) was dissolved in 0.2 M phosphate buffer (pH 6.5, 73 mL) to pH 5.5 and diluted with water (20 mL). The mixture was concentrated to 130 mL, subjected to resin purification (SP207, 260 mL), and eluted with water (238 mL) and 10% aqueous isopropanol (780 mL). The active fractions were collected, concentrated to 30 mL under reduced pressure, activated carbon (purified birch, 87 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The activated carbon was filtered through a membrane filter, and the filtrate was freeze-dried to obtain 4.07 g of amorphous form of Compound (I) (yield 95.7%). Dissolve 0.2 g of this amorphous form of Compound (I) in water (0.8 mL), add isopropanol (1.2 mL) at room temperature, inoculate with Form I crystals (Comparative Example 2a, 1 mg) and stir. The mixture was stirred for 3 hours, and the precipitated crystals were filtered and dried to obtain 0.1 g of Compound I (I) crystals (yield 50%).

Comparative Example 2c
Compound (I) (net 2.113 g) and 0.2 M phosphate buffer (pH 6.5, 73 mL) were alternately added to adjust to pH 4.6, and diluted with water (27 mL). The mixture was concentrated to 80 mL under reduced pressure, adjusted to pH 5.4 with 0.2 M phosphate buffer (pH 6.5, 16 mL), and diluted with water (48 mL). The mixture was subjected to resin purification (SP207, 240 mL) and eluted with water (276 mL) and 10% aqueous isopropanol (720 mL). The active fractions were collected, concentrated under reduced pressure to 12 mL, activated carbon (purified birch, 40 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The activated carbon was filtered through a membrane filter and diluted to 14 mL with water. Form I crystals (Comparative Example 2b, 6 mg) were inoculated into the aqueous solution, and isopropanol (84 mL) was added dropwise over 1 hour to the suspension obtained by stirring with a stirring bar at room temperature. After completion of the dropwise addition, the mixture was stirred for 3 hours, and the precipitated crystals were filtered and dried to obtain 1.834 g of Compound I (I) crystals (yield 86.8%). Moisture: 5.37%, dehydrated content 95.3%, HPLC area ratio 99.3%.

Test Example 1 Powder X-ray Diffraction Measurement Lyophilized composition obtained in Example 1a, Example 1b and Comparative Example 1, crystals obtained in Example 2a and Example 2b, Comparative Example 2a, Comparative Example 2b and Comparative The crystal obtained in Example 2c and sodium chloride were subjected to powder X-ray diffraction measurement under the conditions shown below using a powder X-ray diffractometer (RINT2200: Rigaku).
<Measurement conditions>
X-ray: Cu / 40kV / 40mA
Sample rotation speed: 60 rpm
Divergent slit: 0.5 °
Scattering slit: 0.5 °
Light receiving slit: 0.3 mm
Monochrome light receiving slit: 0.8mm
Sampling width: 0.02 °
Detector: Scintillation counter scan speed: 1 ° / min
Scanning range: 5 ° -40 °

The X-ray diffraction charts of Example 1a, Example 1b, Example 2b, Comparative Example 1, and sodium chloride are shown in FIG. 1, FIG. 2, FIG. 3, FIG. The lyophilized composition obtained in Example 1a and Example 1b was crystalline, and the lyophilized composition obtained in Comparative Example 1 was amorphous. Further, from the X-ray diffraction chart, it was confirmed that the crystal of Example 2b was a Form I crystal of Compound (I). Similarly, the crystals of Example 2a and Comparative Examples 2a to 2c are not shown in the data, but from their X-ray diffraction charts, it was confirmed that they were Form I crystals of Compound (I).
In Examples 2a and 2b and Comparative Examples 2a to 2c, the same type I crystals of the compound (I) were obtained. Therefore, by performing crystallization from an aqueous solution containing sodium chloride, Comparative Examples 2a to 2c were conducted. It was shown that Form I crystals can be produced preferentially without going through the purification by octadecyl silica gel column chromatography or resin.

  In the X-ray diffraction charts of Examples 1a and 1b, a peak that does not exist in Example 2b is observed at 31 to 32 °. This peak is derived from sodium chloride contained in the lyophilized composition because the peak is observed at 31 to 32 ° on the X-ray diffraction chart of sodium chloride (FIG. 5). In the present invention, since the aqueous solution of the compound (I) and the inorganic salt is lyophilized, it can be said that the resulting lyophilized composition contains the inorganic salt. Since the pattern obtained by removing the 31-32 ° peak from the X-ray diffraction charts of Examples 1a and 1b coincides with the pattern of Example 2b, the crystals obtained in Examples 1a and 1b are also I-type crystals. I was able to confirm. On the other hand, when the content of sodium ion and chloride ion of the type I crystal obtained in Example 2b was examined by ion chromatography, it was 0.1% or less. In the present invention, the compound (I) is crystallized from an aqueous solution containing the compound (I) and an inorganic salt, but it is confirmed that the obtained compound (I) crystals do not contain an inorganic salt. did it.

Test Example 2 Stability Evaluation About the crystals obtained in Example 1a and Example 1b and the amorphous lyophilized composition obtained in Comparative Example 1, using a thermo-hygrostat (LH20-12M: Nagano Science) A severe test (2 weeks and 1 month) at 60 ° C. was conducted, and related substances were measured by HPLC method under the following conditions.
<Test conditions>
Column: Warers Atlantis dC18, 5 μm, 4.6 × 250 mm
Column temperature: constant temperature around 35 ° C. Injection volume: 5 μL
Detector: UV absorption photometer (measurement wavelength: 210 nm)
Mobile phase A: Dissolve 1.32 g of diammonium hydrogen phosphate in 900 mL of water, add phosphoric acid to adjust the pH to 3.0, and then add water to make 1000 mL.
Mobile phase B: Acetonitrile gradient program for liquid chromatography: The mixing ratio of mobile phase A and mobile phase B is changed and controlled as follows.
Time after injection (minutes) Mobile phase A (vol%) Mobile phase B (vol%)
0-5 100 0
5-20 100 → 90 0 → 10
20-30 90 10
Flow rate: 1.0 mL / min
Retention time of compound (I): about 6.5 min
Measurement time: 30 min
Table 2 shows the transition of the total amount of related substances in each sample. The crystalline lyophilized composition had less starting material relative to the amorphous lyophilized composition. In addition, the amorphous lyophilized composition significantly increased the amount of the related substance after the severe test, whereas the crystalline lyophilized composition suppressed the increase in the amount of the related substance. From the above results, it was confirmed that the storage stability can be dramatically improved by using Compound (I) as a crystalline lyophilized composition by the method of the present invention.

Reference Example 1 Production Method of Compound (I) Reference Example 1a
tert-butyl {2-[({[(2S, 5R) -6-benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl } Carbamate

(2S, 5R) -6- (Benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxylic acid (4.80 kg, 17.373 mol) in dehydrated ethyl acetate (62 L ) The solution was cooled to −30 ° C., isobutyl chloroformate (2.52 kg) and triethylamine (1.85 kg) were successively added dropwise, and the mixture was stirred at −30 ° C. for 15 minutes. Dehydrated ethyl acetate solution of tert-butyl 2- (aminooxy) ethylcarbamate (15 wt%, 23.45 kg) was added to the reaction solution over 30 minutes (2 L of washed dehydrated ethyl acetate), and the temperature was raised to 0 ° C. over 1 hour. did. The mixture was washed successively with 8% aqueous citric acid solution (65 L), 5% aqueous sodium bicarbonate (60 L), and water (60 L), and concentrated to 24 L. The operation of adding ethyl acetate (24 L) to the concentrate and substituting and concentrating to 24 L was performed twice, and ethyl acetate (29 L) and hexane (72 L) were added to the resulting concentrate, and the mixture was stirred overnight. Hexane (82 L) was added dropwise to the mixture and stirred for 2 hours. The precipitated crystals were collected by filtration, washed with hexane, and dried under vacuum to obtain 5.51 kg of the title compound (yield 76%).
HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 50/50, 1.0 mL / min, UV 210 nm, RT 4.4 min; ¹ HNMR (400 MHz, CDCl ₃ ) δ 1.44 (s , 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 3.03 (br.d., J = 11.6 Hz, 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H) ), 4.90 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 5.44 (br.s., 1H), 7.34-7. 48 (m, 5H), 9.37 (br.s., 1H) ; MS m / z 435 [M + H] +.

Reference Example 1b
tert-butyl {2-[({[(2S, 5R) -6-hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} Carbamate

tert-butyl {2-[({[(2S, 5R) -6-benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl } To a methanol solution (85 L) of carbamate (5.52 kg, 12.705 mol), 10% palladium carbon catalyst (50% water content, 0.55 kg) was added and stirred for 1 hour under hydrogen pressure (0.1 MPa). . The catalyst was filtered and the solid was washed with methanol (25 L). The filtrates were combined and concentrated under reduced pressure to 39 L at a liquid temperature of 10 ° C. or lower. The operation of adding acetonitrile (44 L) to the concentrated liquid and substituting and concentrating to 39 L at a liquid temperature of 10 ° C. or lower was performed twice, and the mixture was cooled to 0 ° C. and stirred overnight. The precipitated crystals were collected by filtration, washed with acetonitrile (24 L), and dried under vacuum to obtain 3.63 kg of the title compound (yield 83%).
HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 75/25, 1.0 mL / min, UV 210 nm, RT 3.9 min; ¹ HNMR (400 MHz, CD ₃ OD) δ1.44 ( s, 9H), 1.73-1.83 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (br. dd., J = 15.0, 7.0 Hz, 1H), 3.03 (d, J = 12.0 Hz, 1H), 3.12 (br.d., J = 12.0 Hz, 1H), 3 .25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS m / z 345 [M + H] ⁺ .

Reference Example 1c
Tetrabutylammonium tert-butyl {2-[({[(2S, 5R) -7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino ) Oxy] ethyl} carbamate

To acetonitrile (51 L), water (51 mL), tert-butyl {2-[({[(2S, 5R) -6-hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2 -Yl] carbonyl} amino) oxy] ethyl} carbamate (3.53 kg, 10.251 mol), sulfur trioxide-pyridine complex (3.95 kg), 2,6-lutidine (2.21 kg) were added in that order. Stir at 45 ° C. overnight. The mixture was filtered to remove insolubles, the solid was washed with acetonitrile (11 L), and the filtrate was combined and concentrated to 17 L. The concentrated solution was cooled to 10 ° C. or lower, separated into 9% sodium dihydrogen phosphate aqueous solution (60 L) and ethyl acetate (113 L), and the organic layer was extracted again with 9% sodium dihydrogen phosphate aqueous solution (11 L). Ethyl acetate (113 L), 30% tetrabutylammonium hydrogensulfate aqueous solution (12.87 kg), and 37% sodium dihydrogenphosphate aqueous solution (56.5 kg) were added to the obtained aqueous layer, and the mixture was stirred for 15 minutes. The organic layer was separated, washed with 20% aqueous sodium dihydrogen phosphate (60 L), dried over anhydrous magnesium sulfate (2.5 kg), filtered, and concentrated under reduced pressure. The crystals of the title compound precipitated in the concentrate were dissolved in ethyl acetate to adjust the total liquid volume to 20 L to obtain 32.55 kg of the ethyl acetate solution of the title compound (net 6.25 kg, yield 92%). This solution was subjected to the next step without further purification.

Reference Example 1d Crude product of compound (I)

Tetrabutylammonium tert-butyl {2-[({[(2S, 5R) -7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino )] Oxy] ethyl} carbamate (788 g, net 467.1 g, 0.701 mol) in dichloromethane (934 mL) was cooled to −20 ° C. under a stream of nitrogen and trifluoroacetic acid (934 mL) was added dropwise over 15 minutes. The temperature was raised to ° C. and stirred for 1 hour. The reaction solution was cooled to −20 ° C., diisopropyl ether (4.17 L) was added dropwise, and the mixture was heated to −6 ° C. and stirred for 1 hour. The precipitate was filtered, suspended and washed with diisopropyl ether (2 × 1 L), and the wet solid was dried in vacuo to give 342.08 g of the title compound (net 222.35 g, yield 98%, HPLC area ratio 96.1%, CE / TFA 27 mol%).

Reference Example 1e
A 0.2M phosphate buffer (pH 6.5, 7.2 L) was cooled to 10 ° C. or lower and stirred with (2S, 5R) -N- (2-aminoethoxy) -7-oxo-6- (sulfooxy). -1,6-diazabicyclo [3.2.1] octane-2-carboxamide (Reference Example 1d Crude product of compound (I), net 1.2 kg) and ice-cooled 0.2 M phosphate buffer (pH 6.5) , 3.5 L) was alternately added little by little to adjust the pH between 4.2 and 4.8, and finally to pH 4.6. The mixture was diluted with water (19.3 L) (total amount: 30 L), and concentrated under reduced pressure to 24 L at a liquid temperature of 18 ° C. or lower. The pH of the concentrate is adjusted to pH 5.4 with 0.2 M phosphate buffer (pH 6.5, 2.4 L), diluted to 43.2 L with water, subjected to purification of the resin (Separbeads SP207, 75 L), and water ( 83 L) and 10% aqueous isopropanol to collect active fractions. The active fractions were combined (33 L), concentrated to 7.2 L at a liquid temperature of 15 ° C. or lower, activated carbon (24 g) was added, and the mixture was stirred for 30 minutes. The activated carbon was filtered through a membrane filter and washed with water (0.4 L × 2). The filtrate was combined, the liquid temperature was adjusted to 20 to 25 ° C., and the type III crystal (3.6 g) obtained according to the method described in Example 7a of Patent Document 6 was inoculated. Isopropanol (50.4 L) was added dropwise to the mixture over 1 hour and stirred overnight. The precipitated crystals were collected by filtration, washed with isopropanol (4.8 L), and dried in vacuo until the product temperature of the wet crystals reached 20 ° C. to obtain 1.17 kg of compound III (III) crystals (yield 90%). .

  According to the present invention, a crystal of compound (I), particularly a single crystal form, particularly a stable form I crystal, can be easily produced on an industrial scale, and a compound having excellent storage stability. It is also possible to provide a lyophilized composition of (I), in particular its single crystal form, in particular of the I form crystal, thus providing a useful process such as an injection of compound (I).

Claims (15)

The following formula (I):

A method for producing a crystal of a compound represented by the formula: wherein the compound is crystallized from an aqueous solution containing the compound and an inorganic salt.   Surface spacing (d) in powder X-ray diffraction pattern 7.34, 5.66, 5.53, 5.30, 5.02, 4.66, 4.37, 4.28, 4.06, 3. Form I of said compound with characteristic peaks at 68, 3.62, 3.47, 3.36, 3.30, 3.16, 3.11, 3.03, 2.99, and 2.50Å The manufacturing method of Claim 1 with which a crystal | crystallization is manufactured.   The production method according to claim 1 or 2, wherein an aqueous solution containing the compound and an inorganic salt is obtained by dissolving the inorganic salt in an aqueous solution of the compound.   The manufacturing method of any one of Claims 1-3 by which the said compound is crystallized by adding a poor solvent to the aqueous solution containing the said compound and inorganic salt.   The manufacturing method of Claim 4 whose said poor solvent is alcohol.   The manufacturing method of any one of Claims 1-3 by which the said compound is crystallized by freeze-drying the aqueous solution containing the said compound and inorganic salt. The following formula (I):

A method for producing a lyophilized composition comprising a compound represented by the formula: wherein the compound is crystallized by the method of claim 1. The following formula (I):

A method for producing a lyophilized composition comprising a compound represented by the formula: wherein the compound is crystallized by lyophilizing an aqueous solution comprising the compound and an inorganic salt.   In the powder X-ray diffraction pattern, the compound has an interplanar spacing (d) of 7.34, 5.66, 5.53, 5.30, 5.02, 4.66, 4.37, 4.28, 4. I with characteristic peaks at 06, 3.68, 3.62, 3.47, 3.36, 3.30, 3.16, 3.11, 3.03, 2.99, and 2.50 Å The manufacturing method of Claim 7 or 8 crystallized to a shape crystal.   The manufacturing method according to any one of claims 7 to 9, wherein an aqueous solution containing the compound and an inorganic salt is obtained by dissolving the inorganic salt in an aqueous solution of the compound.   The manufacturing method according to any one of claims 6 to 10, wherein the heat treatment and refreezing operation of the frozen product are not performed.   The manufacturing method of any one of Claims 1-11 whose said inorganic salt is sodium chloride. A freeze-dried composition comprising crystals of a compound represented by the following formula (I) and an inorganic salt.
  The crystal of the compound has an interplanar spacing (d) of 7.34, 5.66, 5.53, 5.30, 5.02, 4.66, 4.37, 4.28 in a powder X-ray diffraction pattern. Characteristic peaks at 4.06, 3.68, 3.62, 3.47, 3.36, 3.30, 3.16, 3.11, 3.03, 2.99, and 2.50 Å 14. The lyophilized composition according to claim 13, wherein the composition is a form I crystal. The lyophilized composition according to any one of claims 13 to 14, wherein the inorganic salt is sodium chloride.